Chemical targeting of noncanonical secondary structures of DNA and RNA has emerged as a promising approach for therapeutic development. The most promising targets seem to be four-stranded structures in the G-rich regions of the genome, known as G-quadruplexes (G4s), which are associated with important regulatory regions including promoters. In this study, we tested and modeled the binding of five plant-derived secondary metabolites, known for their antiproliferative activity in vitro, to two G4s found in the human genome: the first at the c-Myc proto-oncogene and the second at the human telomere repeat region. Among the tested compounds, brucine exhibited the strongest interaction with both G4 sequences, while ellagic acid demonstrated binding efficacy comparable to that of brucine in the c-Myc sequence. Through molecular dynamics simulations and the Markov state model, we explored the binding modes of these ligands, elucidated the G4 stability in the bound state, and investigated the fluorescence quenching effect of thioflavin T (ThT) upon its displacement. The biological effects of these natural compounds were investigated in human cell lines, and the interaction with G4s was verified experimentally using a fluorescence displacement assay and CD spectroscopy. This study demonstrates the interaction of these natural compounds with the G4 structures and their implications for therapeutic targeting.

BioTechmed Graz Mozartgasse 12 2 Graz 8010 Austria

Brno University of Technology Faculty of Chemistry Purkynova 118 Brno 612 00 Czech Republic

Christian Doppler Laboratory for High Content Structural Biology and Biotechnology Department of Structural and Computational Biology Max Perutz Laboratories University of Vienna Campus Vienna Biocenter 5 Vienna 1030 Austria

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 Brno 612 00 Czech Republic

Laboratory of Computer Aided Molecular Design Division of Medicinal Chemistry Otto Loewi Research Center Medical University of Graz Neue Stiftingtalstrasse 6 3 Graz 8010 Austria

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